Selectively fluorinated organic compounds present a range of interesting and unique properties, particularly attractive to pharmaceutical, material and agricultural sciences. For this reason, development of the synthetic methods for introduction of fluorinated groups into organic molecules has recently become a subject of remarkably growing interest. However, efficient, mild and selective protocols, especially employing transition metal complexes as catalysts, are still rare. For instance, catalytic method for arylation of α,α-difluoroketones requires high palladium and ligand loading to give product, which is moreover hardly separable from the byproduct formed in considerable amounts (Guo, C.; Wang, R.-W.; Qing, F.-L. J. Fluor. Chem., 2012, 143, 135-142). Alternatively, corresponding silyl enol ether can be applied, but addition of toxic tributyltin fluoride is necessary to facilitate transmetallation (Guo, Y.; Shreeve, J. M. Chem. Commun. 2007, 3583-3585).
The present invention provides methods for the synthesis of a wide range of α-aryl and α-heteroaryl α,α-difluoroketones by palladium-catalyzed coupling of aryl and heteroaryl halides with difluoroacetophenones. The products of these reactions can be converted, in addition to alcohols and amines by standard functional group interconversions, to the corresponding difluoromethylarenes by C—C bond cleavage. The reactions occur with an air-stable palladium catalyst and aryl halide as limiting reagent, thereby constituting a practical method to create a large family of difluoroalkylarene and heteroarene derivatives.
Aromatic compounds containing a fluorine atom or a trifluoromethyl group on an aromatic ring are now widespread in medicinal chemistry (Purser, et al., Chem. Soc. Rev., 2008, 37:320; Wang, et al., Chem. Rev., 2014, 114:2432). It is well established that fluorine and trifluoromethyl substituents modulate the lipophilicity and metabolic stability of organic compounds; they also alter the non-covalent interactions of the aryl group, providing a method to affect binding affinities and selectivities (Banks, et al., Organofluorine Compounds: Principles and Commercial Applications; Plenum: New York, 2000; Kirsch, P., Modern Fluoroorganic Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2013). However, compounds containing more complex alkyl groups with fluorine atoms at the benzylic position are less studied because they are challenging to prepare. Reliable methods to form a carbon-carbon bond between an aryl electrophile and a difluoroalkyl nucleophile have not been developed (Feng, et al., Angew. Chem., Int. Ed., 2014, 53:1669).
This limitation on the coupling of aryl electrophiles with fluoroalkyl nucleophiles arises from several properties of fluoroalkyl groups. First, a majority of coupling reactions mediated by transition metal complexes form the aryl-alkyl bond by reductive elimination from an arylmetal alkyl intermediate (Enchavarren, et al., Metal-Catalyzed Cross-Coupling Reactions; Meijere, et al., Eds.; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2008; Vol. 1, p 1), and this reductive elimination is slow when the alkyl group contains fluorine on the carbon. Second, there are few methods to prepare α,α-difluoroalkylmetal reagents (Zemtsov, et al., J. Org. Chem., 2013, 79:818); therefore transition-metal complexes containing an α,α-difluoroalkyl group are rare.
The carbonyl functionality is one of the cornerstones of organic chemistry because it can be transformed into a wide range of functional groups, including alcohols, amines, alkyl groups, and esters. Considering the versatile chemistry of the carbonyl functionality, we considered that an approach to prepare a variety of alkylarenes containing fluorine on the benzylic carbon atom would result from the coupling of aryl halides with fluorinated enolates. This coupling and subsequent derivatization could afford a variety of α-aryl-α,α-difluorocarbonyl compounds. However, the couplings of fluorinated enolates with aryl electrophiles are limited to reactions that require stoichiometric amounts of copper, high temperatures, or both (Fujikawa, et al., Org. Lett., 2011, 13:5560; Guo, et al., J. Fluorine Chem. 2012, 143:135). Because of the severity of these reaction conditions, the scope of these coupling reactions is narrow and does not encompass haloarenes containing many of the common functional groups of medicinally important compounds.